CN1762345A - Silybinin injection and its preparation method - Google Patents
Silybinin injection and its preparation method Download PDFInfo
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- CN1762345A CN1762345A CN 200510094598 CN200510094598A CN1762345A CN 1762345 A CN1762345 A CN 1762345A CN 200510094598 CN200510094598 CN 200510094598 CN 200510094598 A CN200510094598 A CN 200510094598A CN 1762345 A CN1762345 A CN 1762345A
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Abstract
The invention relates to a silybin injection and its preparation method, which comprises silybin meglumine, glucosamine, alkaline amino acid solubiliser and pharmaceutically acceptable solvent, or compound of silybin and alkaline solubiliser and pharmaceutically acceptable solvent, the pH is 4-11. The injection also comprises one or more of pharmaceutically acceptable solubilizer, pH regulator, isotonic conditioning agent, painkiller, anti-oxidant agent, preservative and complexing agent.
Description
Technical field
The present invention belongs to field of pharmaceutical preparations, specifically, relates to a kind of Silybinin injection and preparation method thereof.
Technical background
Silymarin (Silymarin) is through extracting refining gained bulky powder by feverfew Silybum Herba Silybi mariani [Silybum marianum (L.) Gaertn.] fruit, mildly bitter flavor, have and draw moistly, water insoluble, significant protection is arranged and stablize the liver plasma membrane effect; To carbon tetrachloride, all kinds hepatic injury that hepatotoxic agents such as sulfuration acetamide cause has protection and therapeutical effect in various degree, and the rising of the caused alanine aminotransferase of carbon tetrachloride is had certain interception.Clinically be used for sick treatment such as chronic persistent hepatitis, chronic active hepatitis, first cirrhosis, liver poisoning, for the effect that all has clear improvement of symptom, sign, the liver function of acute and chronic hepatitis.Silymarin is the mixture that contains a plurality of components, and wherein silibinin (silybin) is one of its main component.Silibinin and other effective ingredient are all water insoluble, and oral administration biaavailability is lower, and individual variation is bigger, though existing silybin-N-methylglucamine is soluble in water, still can separate out under one's belt, and influence absorbs and curative effect.Injection administration can address the above problem, but document is not seen the report of this respect as yet, main cause is technical difficulty: as the water-soluble vegetable oil that also is insoluble to of silibinin, being difficult to make with water or oil is the injection of carrier, as make that though alkali metal salt can solve the water solublity problem but pH value of aqueous solution is too high, be difficult on the physiology accept, make the salt or the complex of organic base on the other hand, but its stability is bad, and especially the preparation process complex is degraded easily.Silybinin injection of the present invention can address the above problem, and has important clinical significance.
Summary of the invention
In order to overcome the deficiency of prior art, the object of the present invention is to provide a kind of Silybinin injection, said preparation stable in properties, bioavailability height.
Another object of the present invention is to provide a kind of method for preparing above-mentioned Silybinin injection, method is simple for this, helps large-scale production.
The invention provides a kind of Silybinin injection, comprise small-volume injection and infusion solution, contain silibinin and alkaline solubilizing agent and pharmaceutically acceptable solvent; PH value is 4-11, preferred 5-10.
Described alkaline solubilizing agent is selected from meglumine, glucosamine, basic amino acid.The preferred arginine of described basic amino acid, lysine, histidine.
Described injection can be to be the solution of solvent with water, can be to be the solution of solvent with the organic solvent, also can be to be the solution of solvent with water and ORGANIC SOLVENT MIXTURES, and described organic solvent can be pharmaceutically acceptable organic solvent.
Described injection also can contain in pharmaceutically acceptable cosolvent, pH regulator agent, isoosmotic adjusting agent, analgesics, antioxidant, antiseptic and the chelating agent one or more.Described pH regulator agent can be at least a pharmaceutically acceptable conventional substances that is used to regulate pH.For example hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, malic acid, succinic acid, tartaric acid, maleic acid, aminoacid, meglumine, sodium hydroxide, sodium carbonate, sodium bicarbonate and the buffer system that contains above-mentioned substance.Described isoosmotic adjusting agent can be glucose, sodium chloride.Described cosolvent or solubilizing agent are ethanol, propylene glycol, poloxamer, castor oil hydrogenated, surfactant, cyclodextrin, phospholipid.
All kinds of adjuvants are conventional amount used in the described injection.
Small-volume injection of the present invention comprises injecting uses small-volume injection, and faces with preceding with the small-volume injection of infusion again after the dilution of glucose injection or normal saline; Infusion solution of the present invention comprises the glucose injection or the normal saline injection of intravenously administrable.The invention provides a kind of method for preparing Silybinin injection, comprising:
(1) is mixed with the solution that contains silibinin, solubilizing agent with appropriate solvent;
(2) remove according to a conventional method impurity, decolour, remove former, the sterilization.
Described (1) step, can be that described silibinin, alkaline solubilizing agent and required adjuvant are dissolved in water for injection or other solvent, also can be earlier the reflux dissolving in water or ethanol with silibinin and solubilizing agent, remove with pharmacopedics conventional methods such as drying under reduced pressure then and desolvate, again gained solid and required adjuvant are dissolved in water for injection or other solvent.Can the pH value of gained solution be transferred to 4-11 with the pH regulator agent, between the preferred 5-10, can also add described cosolvent, isoosmotic adjusting agent, and pharmaceutically acceptable other adjuvant are as antioxidant, analgesics, antiseptic and/or network mediating recipe etc.Gained solution can be removed impurity according to a conventional method, decolour, removes former, sterilization.
The amount of application of injection of the present invention is treatment hepatopathy effective dose, and according to practical situation adjustment such as the state of an illness and patient's sex, age, body constitution.
Silibinin raw material of the present invention, and adjuvant such as described solubilizing agent, excipient all can directly be buied from market.
Silibinin and other effective ingredient are all water insoluble, and oral administration biaavailability is lower, and individual variation is bigger, though existing silybin-N-methylglucamine is soluble in water, still can separate out under one's belt, influence absorbs, and Silybinin injection can address the above problem, the bioavailability height.
The specific embodiment
By the following examples the present invention is further described, but should by any way it be interpreted as limitation of the present invention.Field of pharmaceutical preparations those skilled in the art are conspicuous to be equal to replacement, and corresponding improvement still falls in the protection domain of the present invention.
Embodiment 1
Get silibinin 48.2 grams, meglumine 19.5 grams, heating for dissolving in ethanol, backflow is spent the night, and evaporated under reduced pressure ethanol gets the silybin meglumine solid.
Get silibinin 48.2 grams, glucosamine 17.9 grams, heating for dissolving in ethanol, backflow is spent the night, and evaporated under reduced pressure ethanol gets silibinin glucosamine solid.
Get silibinin 48.2 grams, arginine 17.4 grams, heating for dissolving in ethanol, backflow is spent the night, and evaporated under reduced pressure ethanol gets silibinin arginine solid.
Embodiment 2
Get an amount of embodiment 1 gained silybin meglumine solid, be dissolved in an amount of water for injection stirring and dissolving, concentration is 5mg/ml, it is an amount of to add cosolvent, transfers pH, adds 0.05% (g/ml) active carbon, be diluted to scale with water for injection, heated and stirred 30 minutes is filtered packing, sterilization gets the silybin meglumine injection.
Embodiment 3
Get an amount of embodiment 1 gained silibinin glucosamine solid, be dissolved in an amount of water for injection stirring and dissolving, concentration is 8mg/ml, it is an amount of to add cosolvent, transfers pH, adds 0.05% (g/ml) active carbon, be diluted to scale with water for injection, heated and stirred 40 minutes is filtered packing, sterilization gets silibinin glucosamine injection.
Embodiment 4
Get an amount of embodiment 1 gained silibinin lysine solid, be dissolved in an amount of water for injection stirring and dissolving, concentration is 5mg/ml, it is an amount of to add cosolvent, transfers pH, adds 0.05% (g/ml) active carbon, be diluted to scale with water for injection, heated and stirred 60 minutes is filtered packing, sterilization gets silibinin lysine injection.
Embodiment 5
Get an amount of embodiment 1 gained silybin meglumine solid, be dissolved in an amount of 0.9% chloride injection water stirring and dissolving, concentration is 5mg/ml, it is an amount of to add cosolvent, transfers pH, adds 0.05% (g/ml) active carbon, be diluted with water to scale with 0.9% chloride injection, heated and stirred 30 minutes is filtered packing, sterilization gets the agent of silybin meglumine chloride injection.
Embodiment 6
Get an amount of embodiment 1 gained silybin meglumine solid, be dissolved in an amount of 5% or 10% glucose injection water stirring and dissolving, concentration is 5mg/ml, it is an amount of to add cosolvent, transfers pH, adds 0.05% (g/ml) active carbon, be diluted with water to scale with 5% or 10% glucose injection, heated and stirred 30 minutes is filtered packing, sterilization gets the agent of silybin meglumine glucose injection.
Embodiment 7
Get an amount of embodiment 1 gained silybin meglumine solid, be dissolved in an amount of sodium chloride-glucose injection water stirring and dissolving, concentration is 5mg/ml, it is an amount of to add cosolvent, transfers pH, adds 0.05% (g/ml) active carbon, be diluted to scale with sodium chloride-glucose injection water water for injection, heated and stirred 30 minutes is filtered packing, sterilization gets silybin meglumine sodium chloride-glucose injection water injection.
Embodiment 8
Get an amount of silybin meglumine solid and an amount of poloxamer and/or alcohol, add an amount of water for injection, stirring is dissolved it fully, with dilute hydrochloric acid pH value is transferred to about 7.5, obtain every milliliter and contain 10 milligrams of silybin meglumines, the solution that poloxamer is 10 milligrams, the amount adding active carbon according to 0.05% (g/ml) is diluted to scale with water for injection, heated and stirred 30 minutes, filter, sterilization gets the silybin meglumine injection.
Embodiment 9: the solubility property of the preparation of the present invention that embodiment 2～5 is made is investigated.After adding water for injection, all fine dissolvings of energy, clarity is qualified.
Embodiment 10: stability test
Investigate embodiment 2～5 obtained stability of formulation with damp and hot accelerated test
Preparation of the present invention placed under 40 ± 1 ℃ the condition,, investigate clarity, pH value, the content of this product through six months.
The study on the stability result
| Project | Preparation | Time (moon) | ||||
| 0 | 1 | 2 | 3 | 6 | ||
| Clarity | Embodiment 2 | Settled solution | Settled solution | Settled solution | Settled solution | Settled solution |
| Embodiment 3 | Settled solution | Settled solution | Settled solution | Settled solution | Settled solution | |
| Embodiment 4 | Settled solution | Settled solution | Settled solution | Settled solution | Settled solution | |
| Embodiment 5 | Settled solution | Settled solution | Settled solution | Settled solution | Settled solution | |
| Embodiment 6 | Settled solution | Settled solution | Settled solution | Settled solution | Settled solution | |
| Embodiment 7 | Settled solution | Settled solution | Settled solution | Settled solution | Settled solution | |
| PH value | Embodiment 2 | 8.05 | 8.08 | 8.00 | 7.96 | 7.90 |
| Embodiment 3 | 8.26 | 8.20 | 8.21 | 8.12 | 8.05 | |
| Embodiment 4 | 8.14 | 8.10 | 8.02 | 8.08 | 7.88 | |
| Embodiment 5 | 8.04 | 8.00 | 7.92 | 7.82 | 7.58 | |
| Embodiment 6 | 7.92 | 7.81 | 7.72 | 7.62 | 7.50 | |
| Embodiment 7 | 7.51 | 7.55 | 7.38 | 7.33 | 7.42 | |
| Content % | Embodiment 2 | 100.5 | 100.1 | 100.9 | 101.2 | 100.0 |
| Embodiment 3 | 99.2 | 100.3 | 99.5 | 99.0 | 99.9 | |
| Embodiment 4 | 102.3 | 102.6 | 102.4 | 101.6 | 101.8 | |
| Embodiment 5 | 99.8 | 99.2 | 99.0 | 98.2 | 97.9 | |
| Embodiment 6 | 99.2 | 98.0 | 97.2 | 97.0 | 96.9 | |
| Embodiment 7 | 98.8 | 99.3 | 98.6 | 98.2 | 98.0 | |
Clarity, pH value are checked according to a conventional method in the last table, and content is measured with reference to the method among the national drug standards WS-10001-(HD-0925)-2002 of National Drug Administration's promulgation.
The result shows, in the study on the stability six months, this product clarity, pH value, content have no significant change, and illustrate that this product is stable.
Claims (11)
1, a kind of Silybinin injection comprises small-volume injection and infusion solution, contains complex and pharmaceutically acceptable solvent that silibinin and alkaline solubilizing agent and pharmaceutically acceptable solvent or silibinin and alkaline solubilizing agent form; PH value is 4-11; Its solvent can be the mixture of water or pharmaceutically acceptable organic solvent or water and pharmaceutically acceptable organic solvent.
2, according to the preparation of claim 1, the pH value that it is characterized in that described solution is in the 5-10 scope.
3, according to the preparation of claim 1, it is characterized in that described alkaline solubilizing agent is selected from the complex of meglumine, glucosamine, basic amino acid or silibinin and alkaline solubilizing agent formation, as silybin meglumine complex, silibinin glucosamine complex, silibinin basic amino acid complex.
4,, it is characterized in that described basic amino acid is selected from arginine, lysine, histidine according to the preparation of claim 3.
5,, it is characterized in that described solution also can contain one or more in pharmaceutically acceptable cosolvent, pH regulator agent, isoosmotic adjusting agent, analgesics, antioxidant, antiseptic and the chelating agent according to the preparation of claim 1.
6,, it is characterized in that described pH regulator agent is hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, malic acid, succinic acid, tartaric acid, maleic acid, aminoacid, meglumine, sodium hydroxide, sodium carbonate, sodium bicarbonate and the buffer system that contains above-mentioned substance according to the preparation of claim 5.
7, according to the preparation of claim 5, wherein said cosolvent is propylene glycol, ethanol, tween, poloxamer, castor oil hydrogenated, surfactant, cyclodextrin, phospholipid.
8, according to the preparation of claim 5, wherein said isoosmotic adjusting agent is glucose, sodium chloride.
9, according to the injection of claim 1, wherein said small-volume injection comprises injecting uses small-volume injection, and faces with preceding with the small-volume injection of infusion again after the dilution of glucose injection or normal saline.
10, according to the injection of claim 1, wherein said infusion solution comprises the glucose injection or the normal saline injection of intravenously administrable.
11, the preparation method of the described injection of claim 1 comprises:
(1) is mixed with the solution that contains silibinin, solubilizing agent with appropriate solvent;
(2) get the silibinin complex, be mixed with the solution that contains silibinin, solubilizing agent with appropriate solvent;
(3) get silybin meglumine, be mixed with the solution that contains silibinin, solubilizing agent with appropriate solvent;
(4) remove impurity, former, the sterilization of decolouring, reduce phlegm and internal heat according to a conventional method.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510094598 CN1762345A (en) | 2005-09-29 | 2005-09-29 | Silybinin injection and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510094598 CN1762345A (en) | 2005-09-29 | 2005-09-29 | Silybinin injection and its preparation method |
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| CN1762345A true CN1762345A (en) | 2006-04-26 |
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| CN 200510094598 Pending CN1762345A (en) | 2005-09-29 | 2005-09-29 | Silybinin injection and its preparation method |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102256502A (en) * | 2008-12-23 | 2011-11-23 | 阿格拉集团公司 | Beer and beer-based beverages and method of modification of polyphenols and silicon content in these beverages |
| CN102309441A (en) * | 2010-07-09 | 2012-01-11 | 天津天士力制药股份有限公司 | Silymarin medicinal composition wrapper and preparation method thereof |
| US9248115B2 (en) | 2007-11-15 | 2016-02-02 | Madaus Gmbh | Silibinin component for the treatment of hepatitis |
| CN106074420A (en) * | 2016-06-21 | 2016-11-09 | 江苏中兴药业有限公司 | A kind of preparation method of the silybin meglumine tablets of high bioavailability |
| CN112587488A (en) * | 2020-12-16 | 2021-04-02 | 福建瑞泰来医药科技有限公司 | Silybin composition and preparation method thereof |
| CN115721721A (en) * | 2021-09-01 | 2023-03-03 | 四川大学 | Drug co-loading nano preparation and preparation method and application thereof |
-
2005
- 2005-09-29 CN CN 200510094598 patent/CN1762345A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9248115B2 (en) | 2007-11-15 | 2016-02-02 | Madaus Gmbh | Silibinin component for the treatment of hepatitis |
| CN102256502A (en) * | 2008-12-23 | 2011-11-23 | 阿格拉集团公司 | Beer and beer-based beverages and method of modification of polyphenols and silicon content in these beverages |
| CN102309441A (en) * | 2010-07-09 | 2012-01-11 | 天津天士力制药股份有限公司 | Silymarin medicinal composition wrapper and preparation method thereof |
| WO2012003804A1 (en) * | 2010-07-09 | 2012-01-12 | 天津天士力制药股份有限公司 | Pharmaceutical composition of silybin and preparation method thereof |
| CN102958510A (en) * | 2010-07-09 | 2013-03-06 | 天士力制药集团股份有限公司 | Pharmaceutical composition of silybin and preparation method thereof |
| CN102309441B (en) * | 2010-07-09 | 2015-07-22 | 天士力制药集团股份有限公司 | Silymarin medicinal composition wrapper and preparation method thereof |
| CN102958510B (en) * | 2010-07-09 | 2015-09-09 | 天士力制药集团股份有限公司 | A kind of Silymarin medicinal composition wrapper and preparation method thereof |
| CN106074420A (en) * | 2016-06-21 | 2016-11-09 | 江苏中兴药业有限公司 | A kind of preparation method of the silybin meglumine tablets of high bioavailability |
| CN106074420B (en) * | 2016-06-21 | 2019-12-03 | 江苏中兴药业有限公司 | A kind of preparation method of the silybin meglumine tablets of high bioavilability |
| CN112587488A (en) * | 2020-12-16 | 2021-04-02 | 福建瑞泰来医药科技有限公司 | Silybin composition and preparation method thereof |
| CN115721721A (en) * | 2021-09-01 | 2023-03-03 | 四川大学 | Drug co-loading nano preparation and preparation method and application thereof |
| CN115721721B (en) * | 2021-09-01 | 2024-03-08 | 四川大学 | Drug co-carried nano preparation and preparation method and application thereof |
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